Controlling Cavitand Conformations for Drug Delivery Studies

描述（由申请人提供）：本提案的一般原理是使用外部刺激（光、小分子和电化学）释放结合在容器分子（空腔）内部的客体分子。本提案的长期目标是开发受控药物输送系统。具有药物递送的精确调节的系统将保护反应性药物，并允许它们以特定的时间间隔（时间控制）施用，从而提高药物治疗的有效性。确定哪些外部刺激源是最有效的，并了解约束客体分子释放的规则将是这项研究的首要任务。的合成和设计的三个类的cavitands包含功能，执行一个明确的结构变化，在外部刺激的存在下。核磁共振，紫外-可见光谱，循环伏安法，质谱和等温量热法都将被用来确定这些系统的结构和动力学。该方案的具体目标如下：1）可控分子空间-设计和合成三类对外界刺激（光、小分子和电化学）敏感的空穴。2)改变形式-探索外部刺激对空腔构象的影响。3)控制功能-确定哪种形式的外部刺激适合于控制空穴区中客体分子的释放。外界刺激能控制空穴分子的功能吗？提出了一种调控空穴区催化功能的策略。开发能够控制药物释放的分子所需的基本知识将从这项研究中获得。本文提出的空穴是重要的生物相关分子如乙酰胆碱的优良宿主。这些分子的受控捕获和释放将帮助我们治疗与大脑中乙酰胆碱缺乏相关的疾病，如阿尔茨海默氏症。拟议的研究培训计划将包括实验室合成，分析化学，在国家和国际会议（戈登，ACS和ISMSC）上的演讲，生物相关领域（生物有机化学和分子生物学）和伦理学课程，赠款写作研讨会和同行评审期刊上的出版物。 公共卫生相关性：研究什么样的外部刺激最适合于释放结合的客体分子及其运作机制将导致新的药物递送系统的发展。客体释放的精确控制将使我们能够解决目前药物递送的时间控制的缺陷（当药物在治疗期间在延长的时间段内或以特定的时间间隔递送时）。药物递送的精确调节将通过稳定反应性（快速代谢的）药物分子、与副作用相比增加治疗活性以及减少每次治疗的药物分布数量来提高药物治疗的有效性。

DESCRIPTION (provided by applicant): The general principle of this proposal is to use external stimuli (light, small molecules and electrochemistry) to release guest molecules bound inside of container molecules (cavitands). The long term objective of this proposal is to develop controlled drug delivery systems. Systems with exact regulation of drug delivery will protect reactive drugs and allow them to be administered at specific time intervals (temporal control) resulting in improved effectiveness of drug therapy. Determining which sources of external stimuli are most affective and understanding the rules that govern the release of bound guest molecules will be paramount to this study. The synthesis and design of three classes of cavitands containing functionality that executes a well-defined structural change in the presence of external stimulus is presented. NMR, UV-Vis spectroscopy, cyclic voltammetry, mass spectrometry and isothermal calorimetry will all be exploited to ascertain the structures and dynamics of these systems. The specific aims of this proposal are as follows: 1) Controlled Molecular Space - design and synthesize three classes of cavitands that are sensitive to external stimuli (light, small molecules and electrochemistry). 2) Altering Form - explore the effects that external stimuli have on cavitand conformations. 3) Controlling Function - determine which forms of external stimuli are suitable to control the release of guest molecules from cavitands. Can external stimulus be used to control the function of cavitand molecules? A strategy is proposed to regulate the catalytic function of a cavitand. The fundamental knowledge required to develop molecules capable of controlled drug release will be gained from this research. The cavitands proposed herein are excellent hosts for important bio-relevant molecules like acetylcholine. The controlled capture and release of these molecules will help us treat diseases such as Alzheimer's that are associated with acetylcholine deficiencies in the brain. The proposed research training program will include laboratory synthesis, analytical chemistry, presentations at national and international conferences (Gordon, ACS and ISMSC), courses in bio-related fields (Bioorganic Chemistry and Molecular Biology) and ethics, grant writing workshops and publication in peer reviewed journals. PUBLIC HEALTH RELEVANCE: The study of what external stimulus is best suited to release bound guest molecules and the mechanism by which it operates will lead to the development of new drug delivery systems. Precise control of guest release will allow us to address the deficiencies of current temporal control of drug delivery (when a drug is delivered over an extended period of time or at specific time intervals during treatment). Exact regulation of drug delivery will result in improved effectiveness of drug therapy by stabilizing reactive (quickly metabolized) drug molecules, increasing therapeutic activity as compared to side effects and reducing the number of drug distributions per treatment.